Organic salts obtained by quaternizing the nitrogen of d-glucosamine, and process for the preparation thereof



United States Patent Como, Italy N0 Drawing. Filed Oct. 23, 1965, Ser. No. 504,210 11 Claims. (Cl. 260-211) The present invention relates to organic salts of D- glucosarnine having striking therapeutic characteristics, and to a process for preparing them.

More particularly, the present invention relates to salts of D-glusocamine obtained by quaternizing the nitrogen of D-glucosamine with monophosphoric, diphosphoric or triphosphoric acids which acids are in turn partially esterified with organic compounds having one or more alcoholic groups. 7

The salts of the present invention are simple salts of D-glucosamine obtained by reacting a free amine base with an acid according to the described techniques, and are not to be confused with phosphoric esters of D-glucosamine.

The salts of the present invention correspond to the general formula:

where Where m is zero, R is rnonovalent; in other cases, R is divalent.

The quaternization takes place according to the following scheme:

HO m L According to the process of the present invention, the starting material D-glucosamine base in its free state having a MP. of 110 C. and specific rotation of [a] =+47.5 (measured at concentration 1, corresponding to 1 g. in 100 ml. of water), consisting of White crystals very soluble in Water. The D-glucosamine base is reacted, in stoichiometric proportions with one of the organic compounds in the form of free acid isolated in a pure state, according to the techniques and conditions disclosed in the examples shown hereinafter by indicative and not limitative way.

The present invention also relates to a process for preparing the aforesaid salts, which comprises the steps of gradually adding small portions of the D-glucosamine base as very pure crystals to stoichiometric proportions of phosphoric esters in aqueous solutions of about 20% by weight concentration by stirring, at a temperature lower than 40 C.; measuring at regular intervals (by a potentio-metric or equivalent system) the pH of the reaction mixture, adding if necessary additional phosphoric acid in order to keep the pH below the predetermined values; maintaining under stirring during an hour after the last addition; filtering and subjecting the filtered reaction mixture to pre-cooling at a predetermined temperature; thereafter lyophilizing the pre-cooled reaction mixture according to known techniques.

By way of illustration the following examples are set forth: they are not limitative and their results are summarized in Table 1. All the parts and percentages are by weight.

Examples 1-11 In a reaction vessel kept in a thermostatic bath there were placed the stated amounts of the partially esterfied phosphoric acid selected, in each case, in the form of about 20% aqueous solutions.

The stated amounts of D-glucosamine base having the composition C=40.21%; H==7.3%; N=7.79%;

O=44.6% (theoretical: C:40.22%; H=7.31%

N=7.82%; O=44.65% were added over a period varying from 30 to minutes, in small portions, with stirring, at the stated temperatures. During the addition, the pH of the reaction mixture was repeatedly measured, since if it was higher than the stated values, additional amounts of the partially esterified phosphoric acid could be added, if necessary. When the addition was completed, the mixture was maintained under stirring for 1 hour, and then diluted with water to obtain solutions of 10% concentration. Thereafter, the mixture was subjected to the pre cooling step at the stated temperature and for the stated period, after which is was subjected to lyophilization in an autoclave under vacuum, according to known techniques. All the salts so obtained are hygroscopic and very soluble in water; they have the physical characteristics recorded in the Table 1 for each example.

TAB LE 1 Esterified acid, weight thereof Base Reaction Pro-cooling Pro-cooling Ex. No. (g.) weight temper. pH temper. 'me Obtained salt (g) 0.) (hrs) 1 Ethanol-betaamine-phosphoric acid, 3. 58 27 6. 45 35 8 Ethanol beta-amine-phosphate of bis- 1.41 g. D-glucosamine.

2 Aneurine chloride monophosphoric 1. 8 -35 5. 13 10 Aneurine chloride ester monophosester, 4 g. phate of mono-D-glucosamine. 3 Aneurine chloride monophosphoric 3.6 20 5. 84 10 Aneurine chloride ester monophosester, 4 g. phate of bis-D-glucosamine.

4 Adenosine-fi-mono-phosphoric acid 3. 6 25 5. 91 18 Adenosine-5-mouophosphate of 3.47 g. bisD-glucosamine.

5 1,6-diphosphric tructose, 3.4 g 3. 6 20 4. 40 20 Fructose-1,6-diphosphate of bis-D glucosarnine.

6 1,(rdiphosphoric fructose, 1.7 g. 3. 6 25 5.91 40 20 FructoseLS-diphosphate 0t tetrakis- D-glucosamine.

7 Cocarboxylase, 2 g 1. 5 29-30 5. 9 35 10 Cocarboxylate of bis-D-glucosamine.

8 Cocarboxylase, 2 g 0. 75 29-30 4. 5 35 10 Cocarhoxylate of mouo-D-glucosamine.

9 Adenosine-tri-phosphoric acid, 2.53 g. 0. 9 28 5. 74 40 18 Adenosine-tri-phosphate of mono-D- glucosamiue.

1O Adenosine-tri-phosphoric acid, 2.53 g 1.8 29 6. 25 --40 18 Adenosine-tri-phosphate of bis-D- glucosarmn' e.

11 Adenosine-tri-phosphorie acid, 2.53 g 2. 7 28 6. 40 18 Adenosine-tri-phosphate of tris-D- glucosamine.

Percent yield, empirical formula, color of Percent Analysis Ex. N0. rnicrocrystals C H P 1 98%, C14H34N3OnP, white Cale 33.67 6. 864 8. 413 6.202

Found 33. l 6. 5 8. 2 6. 19

2 98%, 01.133.51.09 PClS, white Cale 38. 61 5.58 12.05 5.33 Found 38. 2 5. 56 12. l 5. 49

3 97%, CHHHNG 0!; P018, straw-colored Cale 39 6. 001 11 375 4. 91 Found 38. 875 6 11. 29 4. l1

4 99%, CzzHnNrOnP, citr.-yellow Cale 37.445 5.715 13.9 4. 39 Found 37. 25 5. 695 13. 8 4. 32

5 95%, CmHmNgOzaPz, light hazel-brown C810 30. 95 5. 77 4. 011 8. 871

Found 30. 9 5. 72 4 8. 6

6 95%, CzoHasN OazPz, light hazel-brown C816 34. 09 6. 296 5. 305 5. 862

Found 34 6. 245 5. 3 5. 8

7 96%, czrHriNsOnPz 018, white Calc 35.17 5.52 10. 24 7.55

Found 35. 09 5. 50 10. 22 7. 3

8 95%, CmHuNaOuPz 018, White 03.10 33. 77 5. 03 10. 93 9. 74 Found 33. 2 5 10. 89 9. 57

9 97%, CMHZQNBOISPZ, straw-colored Cale 28 4. 25 12.24 13. 54

Found 27. 8 4. 3 12. 02 13. 3

10 97%, C2zH zN7Oz3P3, light OiUZ-YQHQW C810 30. 52 4. 89 11. 33 10. 74

Found 30. 2 4. 71 11. 29 10. 7

11 97%, CzeHssNaOzsPa, citr.-yellow C2110 32. 19 5. 307 10. 72 8. 896 Found 32 5. 18 10. 471 8. 796

All the salts of the present invention are pharmaceuticals controlling the dismetabolic energetic states of the hepatic and/or cardiovascular apparatus, to institute a method of cure which unites in a single salt the active principles having hcpato-protective action, vitaminic action of B type and cardiotrophic action with the D-glucosamine that the organism lacks.

Of course, the practical embodiments of the present invention can vary according to the industrial scale realization and the principles known by those skilled in the art, without departing from the scope of the invention itself.

I claim:

1. Ethanol-beta-amino phosphate of bis-D-glncosamine.

2. Aneurine chloride ester monophosphate of mono-D- glucosaminc.

No references cited.

LEWIS GOTTS, Primary Examiner.

E. L. ROBERTS, Examiner.

J, BROWN, Assistant Examiner. 

1. ETHANOL-BETA-AMINO PHOSPHATE OF BIS-D-GLUCOSAMINE.
 2. ANEURINE CHLORIDE ESTER MONOPHOSPHATE OF MONO-DGLUCOSAMINE. 